ABSTRACT The heart responds to stress through hypertrophic growth of cardiomyocytes and progresses to heart failure when stress is sustained. Our previous studies showed that hypertrophy in response to a variety of stimuli occurs independent of signaling through the calcium/calmodulin dependent protein kinase II (CaMKII) but that progression to heart failure is attenuated when CaMKII is deleted. Inflammation is a key contributor to the adverse remodeling associated with heart failure. The long term objective of this proposal is to demonstrate that CaMKII signaling within cardiomyocytes initiates cardiac inflammation in response to non-ischemic interventions such as pressure overload (TAC) and that this plays a significant role in the development of heart failure. Studies proposed in Aim 1 determine if cardiomyocyte localized CaMKII signaling drives cardiac inflammation using cardiac specific CaMKII knockout mice (CKO) to demonstrate loss of TAC-induced inflammatory gene expression and inflammasome activation. We determine if these responses occur specifically in cardiomyocytes by isolation of adult mouse ventricular myocytes from CTL and CKO mice, and by in situ hybridization and enzymatic assays in tissue sections. CaMKII?C transgenics and mice with cardiac specific KO of the p65 subunit of NFkB are used to further demonstrate involvement of the cardiomyocyte in igniting inflammation. Aim 2 asks whether cardiomyocyte CaMKII signaling contributes to accumulation of inflammatory/immune cells in response to TAC. Work in this aim uses CKO mice to demonstrate that TAC promotes immune cell responses through cardiomyocyte CaMKII initiated signals. Studies focus on macrophages and T-cells, using immunohistochemistry and flow cytometry as well as single cell RNA seq to comprehensively define specific populations of macrophages that accumulate in the heart. Cardiac specific KOs or knockdown of chemokines/cytokines is used to demonstrate that generation of these mediators in cardiomyocytes triggers responses of specific immune cell types. Aim 3 determines if blockade of cardiomyocyte CaMKII-initiated inflammation attenuates adverse remodeling and at what point this needs to be accomplished. Proposed studies use cardiac specific KO or inhibition of selected inflammatory mediators to demonstrate that their formation in cardiomyocytes is critical for development of fibrosis and ventricular dysfunction following TAC. Conditional gene deletion with AAV9 Cre is used to establish the time at which maximal benefit from CaMKII inhibition is achieved. Our findings should significantly impact future research since the cardiomyocyte has not previously been considered as a generator of inflammatory signals, the mechanisms by which inflammatory responses are activated in the absence of ?alarmins? has not heretofore been determined, and the concept that most effective prevention of heart failure development could be achieved by early cardiomyocyte-targeted anti-inflammatory interventions is novel.